Novel substituted indolo 4,3 fg quinolines useful for treating migraine

ABSTRACT

Provided herein are novel ergoline derivatives and pharmaceutical compositions thereof. In other embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, migraine using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of agonizing receptors such as, for example, the 5-HT 1D  and or 5-HT 1B  receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing or inhibiting activity at receptors such as, for example, the 5-HT 2B  receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of regulating serotonin transport using the compounds and compositions disclosed herein.

This application is a continuation of U.S. patent Ser. No. 12/978,314,filed Dec. 23, 2010, which claims priority under 35 U.S.C. §119 (e) fromU.S. Provisional Application Ser. No. 61/289,987, filed Dec. 23, 2009,which are hereby incorporated by reference in their entirety.

FIELD

Provided herein are novel ergoline derivatives and pharmaceuticalcompositions thereof. In other embodiments, provided herein are methodsof treatment, prevention, or amelioration of a variety of medicaldisorders such as, for example, migraine using the compounds andcompositions disclosed herein. In still other embodiments, providedherein are methods of agonizing receptors such as, for example, the5-HT_(1B) and or 5-HT_(1D) receptor using the compounds and compositionsdisclosed herein. In still other embodiments, provided herein aremethods of antagonizing or inhibiting activity at receptors such as, forexample, the 5-HT_(2B) receptor using the compounds and compositionsdisclosed herein. In still other embodiments, provided herein aremethods of regulating serotonin transport using the compounds andcompositions disclosed herein.

BACKGROUND

Many naturally occurring and synthetic ergolines are known to bind in anon-specific manner to receptors for the bioamine neurotransmitters,e.g., dopamine, noradrenaline and serotonin and to function as agonistsor antagonists for these compounds at these receptors. Developingcompounds that are selective or specific for certain specific receptorsallows for achievement of desirable therapeutic actions whileeliminating or reducing unwanted side effects and accordingly is animportant challenge. For example, selective serotonin antagonists havebeen developed for the treatment of migraine and more recently,selective dopamine agonists for the treatment of Parkinson's disease andhyperprolactinemia have been discovered.

However, there is a continuing need for less toxic and more selectiveergoline derivatives to treat a variety of disorders such as, forexample, migraines wherein selective agonism (e.g., 5-HT_(1D) and 5-HT₁)and antagonism (e.g., 5-HT_(2B)) neurotransmitters receptors ispreferable.

SUMMARY

Provided herein are ergoline derivatives which address these and otherneeds. In one aspect, the ergoline derivatives described herein includecompounds of structural Formula (I):

or salts, hydrates or solvates thereof wherein:

R₁ is (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄)perfluoroalkyl;

R₂ is alkyl, substituted alkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇;

R₃ and R₄ are independently hydrogen, deuterium, fluoro, hydroxy ormethoxy;

R₅ is hydrogen, (C₁-C₃) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₃)perfluoroalkyl;

R₆ is

R₇ is (C₁-C₄) alkyl;

R₈ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl orsubstituted benzyl;

R₉ is (C₁-C₄) alkyl or benzyl;

R₁₀ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀;

R₁₁ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃,

R₁₂ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆;

R₁₃ is hydrogen or halogen;

R₁₀₁-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;and

k is 0, 1 or 2;

n is 0, 1, 2 or 3;

provided that when R₁ and R₅ are methyl, R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ andR₁₃ are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not n-butyl, R₈ is not methyl and R₉ is not methyl;

R₇ is not isopropyl, R₈ is not methyl and R₉ is not benzyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not n-propyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not ethyl, R₈ is not hydrogen and R₉ is not isobutyl;

provided that when R₁ and R₅ are methyl, R₃ is —OH, R₂, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

provided that when R₁ and R₅ are methyl, R₃ is —OCH₃, R₂, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

provided that when R₁ and R₅ are methyl, R₂, R₃, R₄, R₁₀, R₁₁ and R₁₂are hydrogen, R₁₃ is bromine and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

provided that when R₁ is n-propyl, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁and R₁₂ are hydrogen, R₁₃ is bromine and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

provided that when R₁ and R₅ are methyl, R₂, R₃, R₄, R₁₀, R₁₁ and R₁₂are hydrogen, R₁₃ is iodine and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is methyl, R₅ is n-propyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ and R₁₃ are hydrogen and R₆is

that:

R₁ is not allyl;

provided that when R₁ is ethyl, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁, R₁₂and R₁₃ are hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

provided that when R₁ is n-propyl, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ is hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl

provided that when R₁ is (C₁-C₄) alkyl and R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ andR₁₃ are hydrogen that:

R₆ is not

provided that when R₁ is CH₂NHMe₂, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

provided that when R₁ is CH₂OCOCH₃, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is CH₂OH, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁, R₁₂and R₁₃ are hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ and R₅ are methyl and R₂, R₃ and R₄ are hydrogenthat: R₆ is not

provided that when R₁ and R₅ are methyl and R₂, R₃ and R₄ are hydrogenthat: R₆ is not

provided that when R₁ and R₅ are methyl and R₂, R₃ and R₄ are hydrogenthat: R₆ is not

In another aspect, the ergoline derivatives described herein includecompounds of structural Formula (II):

or salts, hydrates or solvates thereof wherein:

R₁ is (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄)perfluoroalkyl;

R₂ is alkyl, substituted alkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇;

R₅ is hydrogen, (C₁-C₃) alkyl, substituted (C₁-C₃) alkyl, or (C₁-C₃)perfluoroalkyl;

R₆ is

R₇ is (C₁-C₄) alkyl;

R₈ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl orsubstituted benzyl;

R₉ is (C₁-C₄) alkyl or benzyl;

R₁₀ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀;

R₁₁ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃,

R₁₂ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆;

R₁₃ is hydrogen or halogen;

R₁₀₁-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;and

k is 0, 1 or 2;

n is 0, 1, 2 or 3;

provided that when R₁ and R₅ are methyl, R₂, R₁₀, R₁₁, R₁₂ and R₁₃ arehydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not ethyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not ethyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not n-propyl, R₈ is not methyl and R₉ is not methyl;

R₇ is not isopropyl, R₈ is not methyl and R₉ is not benzyl;

R₇ is not ethyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is allyl, R₅ is methyl, R₂, R₁₀, R₁₁, R₁₂ and R₁₃are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is CH₂OH, R₅ is methyl, R₂, R₁₀, R₁₁, R₁₂ and R₁₃are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is CH₂OH, R₅ is methyl, R₂, R₁₀, R₁₁, and R₁₂ arehydrogen, R₁₃ is bromine and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not sec-butyl.

Also provided are derivatives, including salts, esters, enol ethers,enol esters, solvates, hydrates and prodrugs of the compounds describedherein. Further provided are compositions containing the compoundsprovided herein and a vehicle.

Methods of treating, preventing, or ameliorating medical disorders suchas, for example, migraine, ALS, Parkinson's disease, extra-pyramidaldisorders, depression, nausea, restless legs syndrome, insomnia,aggression, Huntington's disease, dystonia, parsomnia andhyperlactinemia are also provided herein. In practicing the methods,effective amounts of the compounds or compositions containingtherapeutically effective concentrations of the compounds areadministered.

Methods of antagonizing receptors such as, for example, 5-HT_(2A),5-HT_(2B), 5-HT₃ serotonin, D2 and D3 dopamine and A1 and A2 adrenergicreceptors are also provided herein. In practicing the methods, effectiveamounts of the compounds or compositions are administered.

Methods of agonizing receptors such as, for example, 5-HT_(1D),5-HT_(1B), 5-HT_(1F) serotonin receptors are also provided herein. Inpracticing the methods, effective amounts of the compounds orcompositions are administered.

Methods of regulating serotonin transport are also provided herein. Inpracticing the methods, effective amounts of the compounds orcompositions are administered.

Methods of making a compound of structural formula (III) wherein R₁ isbenzyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or allylare also provided herein.

The method comprises contacting dihydroergotamine with alkaline metal inan organic solvent or a mixture of organic solvents to form a solutionand contacting this solution with a halide selected from the groupconsisting of benzyl halide, methyl halide, ethyl halide, n-propylhalide, isopropyl halide, n-butyl halide, isobutyl halide, sec-butylhalide and allyl halide.

DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the inability of 1-methyl-dihydroergotamine toagonize the 5-HT_(2B) receptor and provides a comparison to knownagonists of the 5-HT_(2B) receptor;

FIG. 2 illustrates the ability of 1-methyl-dihydroergotamine toantagonize the 5-HT_(2B) receptor;

FIG. 3 illustrates the ability of 1-methyl-dihydroergotamine to agonizethe 5-HT_(1A) receptor;

FIG. 4 illustrates the ability of 1-methyl-dihydroergotamine toantagonize the 5-HT₇ receptor;

FIG. 5 illustrates the ability of 1-methyl-dihydroergotamine to agonizethe 5-HT_(1B) receptor; and

FIG. 6 illustrates the ability of 1-methyl-dihydroergotamine to agonizethe 5-HT_(1D) receptor.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. In the event that there area plurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

“Alkyl,” by itself or as part of another substituent, refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Theterm “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms (C₁-C₂₀ alkyl). In otherembodiments, an alkyl group comprises from 1 to 10 carbon atoms (C₁-C₁₀alkyl). In still other embodiments, an alkyl group comprises from 1 to 6carbon atoms (C₁-C₆ alkyl).

“Alkanyl,” by itself or as part of another substituent, refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl,” by itself or as part of another substituent, refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl,” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Alkoxy,” by itself or as part of another substituent, refers to aradical of the formula —O—R⁴⁰⁰, where R⁴⁰⁰ is alkyl or substituted alkylas defined herein.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R⁴⁰¹, where R⁴⁰¹ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkylas defined herein. Representative examples include, but are not limitedto formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl,benzoyl, benzylcarbonyl and the like.

“Aryl,” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem, as defined herein. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms (C₆-C₂₀aryl). In other embodiments, an aryl group comprises from 6 to 15 carbonatoms (C₆-C₁₅ aryl). In still other embodiments, an aryl group comprisesfrom 6 to 15 carbon atoms (C₆-C₁₀ aryl).

“Arylalkyl,” by itself or as part of another substituent, refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group as, as defined herein. Typical arylalkyl groups include,but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl,naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specificalkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyland/or arylalkynyl is used. In some embodiments, an arylalkyl group is(C₆-C₃₀) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₁₀) alkyl and the aryl moiety is (C₆-C₂₀) aryl.In other embodiments, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g.,the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₈)alkyl and the aryl moiety is (C₆-C₁₂) aryl. In still other embodiments,an arylalkyl group is (C₆-C₁₅) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₅) alkyl and the arylmoiety is (C₆-C₁₀) aryl.

“Compounds” refers to compounds encompassed by structural formulaedisclosed herein and includes any specific compounds within theseformulae whose structure is disclosed herein. Compounds may beidentified either by their chemical structure and/or chemical name. Whenthe chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound. Thecompounds described herein may contain one or more chiral centers and/ordouble bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds may alsoexist in several tautomeric forms including the enol form, the keto formand mixtures thereof. Accordingly, the chemical structures depictedherein encompass all possible tautomeric forms of the illustratedcompounds. The compounds described also include isotopically labeledcompounds where one or more atoms have an atomic mass different from theatomic mass conventionally found in nature. Examples of isotopes thatmay be incorporated into the compounds of the invention include, but arenot limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds mayexist in unsolvated or unhydrated forms as well as solvated forms,including hydrated forms and as N-oxides. In general, compounds may behydrated, solvated or N-oxides. Certain compounds may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated herein and are intended to bewithin the scope of the present invention. Further, it should beunderstood, when partial structures of the compounds are illustrated,that brackets indicate the point of attachment of the partial structureto the rest of the molecule.

“Halo,” by itself or as part of another substituent refers to a radical—F, —Cl, —Br or —I.

“Heteroalkyl,” “Heteroalkanyl,” “Heteroalkenyl” and “Heteroalkynyl,” bythemselves or as part of other substituents, refer to alkyl, alkanyl,alkenyl and alkynyl groups, respectively, in which one or more of thecarbon atoms (and optionally any associated hydrogen atoms), are each,independently of one another, replaced with the same or differentheteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomicgroups which can replace the carbon atoms include, but are not limitedto, —O—, —S—, —N—, —Si—, —NH—, —S(O)—, —S(O)₂—, —S(O)NH—, —S(O)₂NH— andthe like and combinations thereof. The heteroatoms or heteroatomicgroups may be placed at any interior position of the alkyl, alkenyl oralkynyl groups. Typical heteroatomic groups which can be included inthese groups include, but are not limited to, —O—, —S—, —O—O—, —S—S—,—O—S—, —NR⁵⁰¹R⁵⁰²—, ═N—N═, —N═N—, —N═N—NR⁵⁰³R⁴⁰⁴, —PR⁵⁰⁵—, —P(O)₂—,—POR⁵⁰⁶—, —O—P(O)₂—, —SO—, —SO₂—, —SnR⁵⁰⁷R⁵⁰⁸— and the like, where R⁵⁰¹,R⁵⁰², R⁵⁰³, R⁵⁰⁴, R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷ and R⁵⁰⁸ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl.

“Heteroaryl,” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring systems, asdefined herein. Typical heteroaryl groups include, but are not limitedto, groups derived from acridine, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In some embodiments, the heteroaryl group comprises from 5 to 20ring atoms (5-20 membered heteroaryl). In other embodiments, theheteroaryl group comprises from 5 to 10 ring atoms (5-10 memberedheteroaryl). Exemplary heteroaryl groups include those derived fromfuran, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole,indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole andpyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In some embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In other embodiments,the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety is (C₁-C₃) alkyl and the heteroarylmoiety is a 5-10 membered heteroaryl.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Typicalparent aromatic ring systems include, but are not limited to,aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexylene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene and the like.

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms (and optionally any associatedhydrogen atoms) are each independently replaced with the same ordifferent heteroatom. Typical heteroatoms to replace the carbon atomsinclude, but are not limited to, N, P, O, S, Si, etc. Specificallyincluded within the definition of “parent heteroaromatic ring system”are fused ring systems in which one or more of the rings are aromaticand one or more of the rings are saturated or unsaturated, such as, forexample, benzodioxan, benzofuran, chromane, chromene, indole, indoline,xanthene, etc. Typical parent heteroaromatic ring systems include, butare not limited to, arsindole, carbazole, β-carboline, chromane,chromene, cinnoline, furan, imidazole, indazole, indole, indoline,indolizine, isobenzofuran, isochromene, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene and the like.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease). The application of a therapeutic forpreventing or prevention of a diease of disorder is known as‘prophylaxis.’ In some embodiments, the compounds provided hereinprovide superior prophylaxis because of lower long term side effectsover long time periods.

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group during chemical synthesis. Examplesof protecting groups can be found in Green et al., “Protective Groups inOrganic Chemistry”, (Wiley, 2^(nd) ed. 1991) and Harrison et al.,“Compendium of Synthetic Organic Methods”, Vols. 1-8 (John Wiley andSons, 1971-1996). Representative amino protecting groups include, butare not limited to, formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl(“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substitutedtrityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxyprotecting groups include, but are not limited to, those where thehydroxy group is either acylated or alkylated such as benzyl, and tritylethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers and allyl ethers.

“Salt” refers to a salt of a compound, which possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Substituted,” when used to modify a specified group or radical, meansthat one or more hydrogen atoms of the specified group or radical areeach, independently of one another, replaced with the same or differentsubstituent(s). Substituent groups useful for substituting saturatedcarbon atoms in the specified group or radical include, but are notlimited to —R^(a), halo, —O⁻, ═O, —OR^(b), —SR^(b), —S⁻, ═S,—NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)s are taken together with the nitrogen atomto which they are bonded form a 4-, 5-, 6- or 7-memberedcycloheteroalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S. As specific examples, —NR^(c)R^(c) is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl and N-morpholinyl.

Similarly, substituent groups useful for substituting unsaturated carbonatoms in the specified group or radical include, but are not limited to,—R^(a), halo, —O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl,—CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)₂R^(b), —S(O)₂O⁻,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O⁻, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined.

Substituent groups useful for substituting nitrogen atoms in heteroalkyland cycloheteroalkyl groups include, but are not limited to, —R^(a),—O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl, —CF₃, —CN, —NO,—NO₂, —S(O)₂R^(b), —S(O)₂O⁻, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻,—OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)),—C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b), —C(S)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b),—OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b),—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined.

Substituent groups from the above lists useful for substituting otherspecified groups or atoms will be apparent to those of skill in the art.

The substituents used to substitute a specified group can be furthersubstituted, typically with one or more of the same or different groupsselected from the various groups specified above.

“Subject,” “individual” or “patient” is used interchangeably herein andrefers to a vertebrate, preferably a mammal Mammals include, but are notlimited to, murines, rodents, simians, humans, farm animals, sportanimals and pets.

“Treating” or “treatment” of any disease or disorder refers, in someembodiments, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof,). Treatment may also be considered to includepreemptive or prophylactic administration to ameliorate, arrest orprevent the development of the disease or at least one of the clinicalsymptoms. In a further feature the treatment rendered has lowerpotential for longterm side effects over multiple years. In otherembodiments “treating” or “treatment” refers to ameliorating at leastone physical parameter, which may not be discernible by the patient. Inyet other embodiments, “treating” or “treatment” refers to inhibitingthe disease or disorder, either physically, (e.g., stabilization of adiscernible symptom), physiologically, (e.g., stabilization of aphysical parameter) or both. In yet other embodiments, “treating” or“treatment” refers to delaying the onset of the disease or disorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, adsorption, distribution, metabolism andexcretion etc., of the patient to be treated.

“Vehicle” refers to a diluent, excipient or carrier with which acompound is administered to a subject.

B. Compounds

The compounds described herein include compounds of structural formula(I):

or salts, hydrates or solvates thereof wherein:

R₁ is (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄)perfluoroalkyl;

R₂ is alkyl, substituted alkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇;

R₃ and R₄ are independently hydrogen, deuterium, fluoro, hydroxy ormethoxy;

R₅ is hydrogen, (C₁-C₃) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₃)perfluoroalkyl;

R₆ is

R₇ is (C₁-C₄) alkyl;

R₈ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl orsubstituted benzyl;

R₉ is (C₁-C₄) alkyl or benzyl;

R₁₀ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀;

R₁₁ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃,

R₁₂ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆;

R₁₃ is hydrogen or halogen;

R₁₀₁-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;and

k is 0, 1 or 2;

n is 0, 1, 2 or 3;

provided that when R₁ and R₅ are methyl, R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ andR₁₃ are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not n-butyl, R₈ is not methyl and R₉ is not methyl;

R₇ is not isopropyl, R₈ is not methyl and R₉ is not benzyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not n-propyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not ethyl, R₈ is not hydrogen and R₉ is not isobutyl;

provided that when R₁ and R₅ are methyl, R₃ is —OH, R₂, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

provided that when R₁ and R₅ are methyl, R₃ is —OCH₃, R₂, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

provided that when R₁ and R₅ are methyl, R₂, R₃, R₄, R₁₀, R₁₁ and R₁₂are hydrogen, R₁₃ is bromine and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

provided that when R₁ is n-propyl, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁and R₁₂ are hydrogen, R₁₃ is bromine and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

provided that when R₁ and R₅ are methyl, R₂, R₃, R₄, R₁₀, R₁₁ and R₁₂are hydrogen, R₁₃ is iodine and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is methyl, R₅ is n-propyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ and R₁₃ are hydrogen and R₆is

that:

R₁ is not allyl;

provided that when R₁ is ethyl, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁, R₁₂and R₁₃ are hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

provided that when R₁ is n-propyl, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ is hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl

provided that when R₁ is (C₁-C₄) alkyl and R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ andR₁₃ are hydrogen that:

R₆ is not

provided that when R₁ is CH₂NHMe₂, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

provided that when R₁ is CH₂OCOCH₃, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is CH₂OH, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁, R₁₂and R₁₃ are hydrogen and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ and R₅ are methyl and R₂, R₃ and R₄ are hydrogenthat: R₆ is not

provided that when R₁ and R₅ are methyl and R₂, R₃ and R₄ are hydrogenthat: R₆ is not

provided that when R₁ and R₅ are methyl and R₂, R₃ and R₄ are hydrogenthat: R₆ is not

In some embodiments, R₁ is (C₁-C₃) alkyl, (C₁-C₃) substituted alkyl or(C₁-C₃) perfluoroalkyl. In other embodiments, R₁ is (C₁-C₄) alkyl or(C₁-C₄) perfluoroalkyl. In still other embodiments, R₁ is —CH₃, —C₂H₅,—C₃H₇, i-C₃H₇, —CF₃, —C₂F₅, —C₃F₇ or i-C₃F₇. In still other embodiments,R₁ is —CH₃, —C₂H₅, —C₃H₇, —CF₃, —C₂F₅ or —C₃F₇.

In some embodiments, R₂ is (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,(C₁-C₄) acyl, (C₁-C₄) substituted acyl, halo, (C₁-C₄) heteroalkyl,(C₁-C₄) substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁,—NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇. In other embodiments, R₂is (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl, (C₁-C₄) acyl, (C₁-C₄)substituted acyl, halo, —NO₂, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆or —O₂CR₁₀₇. In still other embodiments, R₂ is (C₁-C₂) alkyl, (C₁-C₂)substituted alkyl, halo, —NO₂, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅,—CO₂R₁₀₆ or —O₂CR₁₀₇.

In some embodiments, n is 0 or 1. In other embodiments, n is 0.

In some embodiments, R₄ is hydrogen. In other embodiments, R₃ and R₄ arehydrogen. In still other embodiments, R₃ and R₄ are deuterium.

In some embodiments, R₅ is —CH₃, —C₂H₅, —C₃H₇, —CF₃, —C₂F₅ or —C₃F₇. Inother embodiments, R₅ is —CH₃ or —CF₃.

In some embodiments, R₆ is

In some embodiments, R₇ is methyl, ethyl or isopropyl. In otherembodiments, R₈ is hydrogen or methyl. In still other embodiments, R₉ isn-propyl, isopropyl, sec-butyl, isobutyl or benzyl. In some embodiments,R₁₀, R₁₁ and R₁₂ are independently hydrogen, OH or (C₁-C₄) alkyl. Inother embodiments, R₁₀, R₁₁ and R₁₂ are hydrogen.

In some embodiments, R₁₃ is hydrogen or bromine.

In some embodiments, R₁ is (C₁-C₄) alkyl or (C₁-C₄) perfluoroalkyl andR₁₃ is hydrogen or bromine. In other embodiments, R₁ is —CH₃, —C₂H₅,—C₃H₇, i-C₃H₇, —CF₃, —C₂F₅, —C₃F₇ or i-C₃F₇ and R₁₃ is hydrogen orbromine

In some embodiments, R₁ is (C₁-C₄) alkyl or (C₁-C₄) perfluoroalkyl andR₆ is

In some of these embodiments, R₇ is methyl, ethyl or ispropyl, R₈ ishydrogen or methyl, R₉ is n-propyl, isopropyl, sec-butyl, isobutyl orbenzyl. In some of the above embodiments, R₁₀, R₁₁ and R₁₂ areindependently hydrogen, OH or (C₁-C₄) alkyl. In still other of the aboveembodiments, R₁₀, R₁₁ and R₁₂ are hydrogen. In still other of the aboveembodiments, R₂ is (C₁-C₂) alkyl, (C₁-C₂) substituted alkyl, halo, —NO₂,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇. In still otherof the above embodiments, n is 0 or 1. In still other of the aboveembodiments, n is 0. In still other of the above embodiments, R₃ and R₄are deuterium. In still other of the above embodiments, n is 0. In stillother of the above embodiments, R₃ and R₄ are hydrogen.

In some embodiments, R₁ is —CH₃, —C₂H₅, —C₃H₇, i-C₃H₇, —CF₃, —C₂F₅,—C₃F₇ or i-C₃F₇ and R₆ is

In some of these embodiments, R₇ is methyl, ethyl or ispropyl, R₈ ishydrogen or methyl, R₉ is n-propyl, isopropyl, sec-butyl, isobutyl orbenzyl. In some of the above embodiments, R₁₀, R₁₁ and R₁₂ areindependently hydrogen, OH or (C₁-C₄) alkyl. In still other of the aboveembodiments, R₁₀, R₁₁ and R₁₂ are hydrogen. In still other of the aboveembodiments, R₂ is (C₁-C₂) alkyl, (C₁-C₂) substituted alkyl, halo, —NO₂,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇. In still otherof the above embodiments, n is 0 or 1. In still other of the aboveembodiments, n is 0. In still other of the above embodiments, R₃ and R₄are deuterium. In still other of the above embodiments, n is 0. In stillother of the above embodiments, R₃ and R₄ are hydrogen.

In some embodiments of a compound of Formula (I): R₁ is —CH₃, —C₂H₅,—C₃H₇, i-C₃H₇, —CF₃, —C₂F₅, —C₃F₇ or i-C₃F₇, R₂ is (C₁-C₄) alkyl,(C₁-C₄) substituted alkyl, (C₁-C₄) acyl, (C₁-C₄) substituted acyl, halo,—NO₂, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇, n is 0 or1, R₃ and R₄ are independently hydrogen or deuterium, R₅ is —CH₃, —C₂H₅,—C₃H₇, —CF₃, C₂F₅ or —C₃F₇, R₆ is

R₁₀, R₁₁ and R₁₂ are independently hydrogen, OH or (C₁-C₄) alkyl; andR₁₃ is hydrogen or bromine

In other embodiments of a compound of Formula (I), R₁ is CH₃, —C₂H₅,-nC₃H₇, —CF₃, C₂F₅ or -nC₃F₇, R₂ is C₁-C₂) alkyl, (C₁-C₂) substitutedalkyl, halo, —NO₂, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or—O₂CR₁₀₇, n is 0; R₃ and R₄ are independently hydrogen or deuterium, R₅is —CH₃ or —CF₃, R₆ is

R₇ is methyl, ethyl or isopropyl, R₈ is hydrogen or methyl, R₉ isn-propyl, isopropyl, sec-butyl, isobutyl or benzyl, R₁₀, R₁₁ and R₁₂ arehydrogen; and R₁₃ is hydrogen.

The compounds described herein include compounds of structural formula(II):

or salts, hydrates or solvates thereof wherein:

R₁ is (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄)perfluoroalkyl;

R₂ is alkyl, substituted alkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇;

R₅ is hydrogen, (C₁-C₃) alkyl, substituted (C₁-C₃) alkyl, or (C₁-C₃)perfluoroalkyl;

R₆ is

R₇ is (C₁-C₄) alkyl;

R₈ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl orsubstituted benzyl;

R₉ is (C₁-C₄) alkyl or benzyl;

R₁₀ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀;

R₁₁ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃

R₁₂ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆;

R₁₃ is hydrogen or halogen;

R₁₀₁-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;and

k is 0, 1 or 2;

n is 0, 1, 2 or 3;

provided that when R₁ and R₅ are methyl, R₂, R₁₀, R₁₁, R₁₂ and R₁₃ arehydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not benzyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not methyl, R₈ is not hydrogen and R₉ is not sec-butyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not ethyl, R₈ is not hydrogen and R₉ is not isobutyl;

R₇ is not ethyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;

R₇ is not n-propyl, R₈ is not methyl and R₉ is not methyl;

R₇ is not isopropyl, R₈ is not methyl and R₉ is not benzyl;

R₇ is not ethyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is allyl, R₅ is methyl, R₂, R₁₀, R₁₁, R₁₂ and R₁₃are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is CH₂OH, R₅ is methyl, R₂, R₁₀, R₁₁, R₁₂ and R₁₃are hydrogen and R₆ is

that:

R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl;

provided that when R₁ is CH₂OH, R₅ is methyl, R₂, R₁₀, R₁₁, and R₁₂ arehydrogen, R₁₃ is bromine and R₆ is

that:

R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not sec-butyl.

In some embodiments, R₁ is (C₁-C₃) alkyl, (C₁-C₃) substituted alkyl or(C₁-C₃) perfluoroalkyl. In other embodiments, R₁ is (C₁-C₄) alkyl or(C₁-C₄) perfluoroalkyl. In still other embodiments, R₁ is —CH₃, —C₂H₅,—C₃H₇, i-C₃H₇, —CF₃, —C₂F₅, —C₃F₇ or i-C₃F₇. In still other embodiments,R₁ is CH₃, —C₂H₅, —C₃H₇, —CF₃, C₂F₅ or —C₃F₇.

In some embodiments, R₂ is (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,(C₁-C₄) acyl, (C₁-C₄) substituted acyl, halo, (C₁-C₄) heteroalkyl,(C₁-C₄) substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁,—NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇. In other embodiments, R₂is (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl, (C₁-C₄) acyl, (C₁-C₄)substituted acyl, halo, —NO₂, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆or —O₂CR₁₀₇. In still other embodiments, R₂ is (C₁-C₂) alkyl, (C₁-C₂)substituted alkyl, halo, —NO₂, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅,—CO₂R₁₀₆ or —O₂CR₁₀₇.

In some embodiments, n is 0 or 1. In other embodiments, n is 0.

In some embodiments, R₅ is —CH₃, —C₂H₅, —C₃H₇, —CF₃, C₂F₅ or —C₃F₇. Inother embodiments, R₅ is —CH₃ or —CF₃.

In some embodiments, R₆ is

In some embodiments, R₇ is methyl, ethyl or isopropyl. In otherembodiments, R₈ is hydrogen or methyl. In still other embodiments, R₉ isn-propyl, isopropyl, sec-butyl, isobutyl or benzyl. In some embodiments,R₁₀, R₁₁ and R₁₂ are independently hydrogen, OH or (C₁-C₄) alkyl. Inother embodiments, R₁₀, R₁₁ and R₁₂ are hydrogen.

In some embodiments, R₁₃ is hydrogen or bromine.

In some embodiments, R₁ is (C₁-C₄) alkyl or (C₁-C₄) perfluoroalkyl andR₁₃ is hydrogen or bromine. In other embodiments, R₁ is —CH₃, —C₂H₅,—C₃H₇, i-C₃H₇, —CF₃, —C₂F₅, —C₃F₇ or i-C₃F₇ and R₁₃ is hydrogen orbromine.

In some embodiments, R₁ is (C₁-C₄) alkyl or (C₁-C₄) perfluoroalkyl andR₆ is

In some of these embodiments, R₇ is methyl, ethyl or ispropyl, R₈ ishydrogen or methyl, R₉ is n-propyl, isopropyl, sec-butyl, isobutyl orbenzyl. In some of the above embodiments, R₁₀, R₁₁ and R₁₂ areindependently hydrogen, OH or (C₁-C₄) alkyl. In still other of the aboveembodiments, R₁₀, R₁₁ and R₁₂ are hydrogen. In still other of the aboveembodiments, R₂ is (C₁-C₂) alkyl, (C₁-C₂) substituted alkyl, halo, —NO₂,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇. In still otherof the above embodiments, n is 0 or 1. In still other of the aboveembodiments, n is 0. I In still other of the above embodiments, n is 0.

In some embodiments, R₁ is —CH₃, —C₂H₅, —C₃H₇, i-C₃H₇, —CF₃, —C₂F₅,—C₃F₇ or i-C₃F₇ and R₆ is

In some of these embodiments, R₇ is methyl, ethyl or ispropyl, R₈ ishydrogen or methyl, R₉ is n-propyl, isopropyl, sec-butyl, isobutyl orbenzyl. In some of the above embodiments, R₁₀, R₁₁ and R₁₂ areindependently hydrogen, OH or (C₁-C₄) alkyl. In still other of the aboveembodiments, R₁₀, R₁₁ and R₁₂ are hydrogen. In still other of the aboveembodiments, R₂ is (C₁-C₂) alkyl, (C₁-C₂) substituted alkyl, halo, —NO₂,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇. In still otherof the above embodiments, n is 0 or 1. In still other of the aboveembodiments, n is 0. In still other of the above embodiments, n is 0.

In some embodiments of a compound of Formula (II): R₁ is —CH₃, —C₂H₅,—C₃H₇, i-C₃H₇, —CF₃, —C₂F₅, —C₃F₇ or i-C₃F₇, R₂ is (C₁-C₄) alkyl,(C₁-C₄) substituted alkyl, (C₁-C₄) acyl, (C₁-C₄) substituted acyl, halo,—NO₂, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇, n is 0 or1, R₅ is —CH₃, —C₂H₅, —C₃H₇, —CF₃, C₂F₅ or —C₃F₇, R₆ is

R₁₀, R₁₁ and R₁₂ are independently hydrogen, OH or (C₁-C₄) alkyl; andR₁₃ is hydrogen or bromine

In other embodiments of a compound of Formula (I), R₁ is CH₃, —C₂H₅,-nC₃H₇, —CF₃, C₂F₅ or -nC₃F₇, R₂ is C₁-C₂) alkyl, (C₁-C₂) substitutedalkyl, halo, —NO₂, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or—O₂CR₁₀₇; n is 0, R₅ is —CH₃ or —CF₃; R₆ is

R₇ is methyl, ethyl or isopropyl, R₈ is hydrogen or methyl, R₉ isn-propyl, isopropyl, sec-butyl, isobutyl or benzyl; R₁₀, R₁₁ and R₁₂ arehydrogen; and R₁₃ is hydrogen.

Exemplary compound of Formula (I) include the compounds in the tablebelow:

Exemplary compounds of Formula (II) include, for example, the8,9-dihydro analogues of many of the above depicted compounds of Formula(I).

Preparation of the Compounds

Exemplary methods for the preparation of compounds of Formula (I) and(II) for use in the compositions and methods provided herein aredescribed below and in the Examples but other methods known in the artcan be used to prepare the ergoline derivatives disclosed herein.

Carboxylic acids (IV) and (V) can be prepared by methods well known tothose of skill in the art.

Many methods exist for conversion of carboxylic (IV) and (V) to amides(I) and (II), respectively. Accordingly, preparation of amides (I) and(II) from carboxylic acids (I) and (II) are well within the ambit of theskilled artisan.

In some embodiments, a method of making a compound of structural formula(III) is provided. The method includes a step of contactingdihydroergotamine with alkaline metal in an organic solvent or a mixtureof organic solvents to form a solution and contacting the solution withan alkyl halide selected from the group consisting of benzyl halide,substituted benzyl halide, allyl halide, homallyl halide, substitutedallyl halide, methyl halide, ethyl halide, propyl halide, isopropylhalide, butyl halide, isobutyl halide and sec-butyl halide to providethe compound of Formula (III) below.

where R₁ is benzyl, substituted benzyl, allyl, substituted allyl,homoallyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl orsec-butyl.

In some embodiments, the halide is iodide. In other embodiments, thehalide is dissolved in a solvent. In still other embodiments, thesolvent is diethyl ether. In still other embodiments, the halide isadded dropwise over a period of time.

In some embodiments, the organic solvent or mixture of organic solventsis a mixture of liquid ammonia, absolute ethanol and ether. In otherembodiments, the temperature of alkaline metal in the organic solvent orthe mixture of organic solvents is between about −78° C. and about −50°C. In still other embodiments, the temperature of alkaline metal in theorganic solvent or the mixture of organic solvents is about −78° C. Instill other embodiments, the alkaline metal is sodium.

In some embodiments, the ratio of liquid ammonia, ether and absoluteethanol is between about 8:2:1 and about 5:1:1. In other embodiments,the ratio of liquid ammonia, ether and absolute ethanol is about6.5:1.33:1. In still other embodiments, the molar ratio of alkalinemetal to dihydroergotamine is between about 20:1 and about 5:1. In stillother embodiments, the molar ratio of alkaline metal todihydroergotamine is about 10:1. In still other embodiments, the molarratio of alkyl halide to dihydroergotamine is between about 10:1 andabout 2.5:1. In still other embodiments, the molar ratio of alkyl halideto dihydroergotamine is about 5:1.

In some embodiments, the alkyl halide is methyl iodide, the alkalinemetal is sodium, the ratio of liquid ammonia, ether and absolute ethanolis about 6.5:1.33:1, the temperature of sodium in liquid ammonia, etherand absolute ethanol is about −78° C., the molar ratio of sodium todihydroergotamine is about 10:1 and the molar ratio of methyl halide todihydroergotamine is about 5:1. In other embodiments, methyl iodide isdissolved in diethyl ether and added dropwise over about a 15 minuteperiod.

Pharmaceutical Compositions and Methods of Administration

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of the compounds provided herein thatare useful in the prevention, treatment, or amelioration of one or moreof the symptoms of diseases or disorders described herein and apharmaceutically acceptable vehicle. Pharmaceutical vehicles suitablefor administration of the compounds provided herein include any suchcarriers known to those skilled in the art to be suitable for theparticular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients.

The compositions contain one or more compounds provided herein. Thecompounds are, in some embodiments, formulated into suitablepharmaceutical preparations such as solutions, suspensions, tablets,dispersible tablets, pills, capsules, powders, sustained releaseformulations or elixirs, for oral administration or in sterile solutionsor suspensions for parenteral administration, as well as topicaladministration, transdermal administration and inhaled administrationvia nebulizers, pressurized metered dose inhalers and dry powderinhalers. In some embodiments, the compounds described above areformulated into pharmaceutical compositions using techniques andprocedures well known in the art (see, e.g., Ansel Introduction toPharmaceutical Dosage Forms, Seventh Edition (1999).

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable derivatives thereof is (are) mixed with asuitable pharmaceutical vehicle. The compounds may be derivatized as thecorresponding salts, esters, enol ethers or esters, acetals, ketals,orthoesters, hemiacetals, hemiketals, acids, bases, solvates, ion-pairs,hydrates or prodrugs prior to formulation, as described above. Theconcentrations of the compounds in the compositions are effective fordelivery of an amount, upon administration that treats, leads toprevention, or amelioration of one or more of the symptoms of diseasesor disorders described herein. In some embodiments, the compositions areformulated for single dosage administration. To formulate a composition,the weight fraction of a compound is dissolved, suspended, dispersed orotherwise mixed in a selected vehicle at an effective concentration suchthat the treated condition is relieved, prevented, or one or moresymptoms are ameliorated.

The active compound is included in the pharmaceutically acceptablevehicle in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems well known tothose of skill in the art and then extrapolated therefrom for dosagesfor humans. Human doses are then typically fine-tuned in clinical trialsand titrated to response.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical characteristics of the compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to ameliorate one or more of the symptoms ofdiseases or disorders as described herein.

In some embodiments, a therapeutically effective dosage should produce aserum concentration of active ingredient of from about 0.001 ng/ml toabout 50-200 μg/ml. The pharmaceutical compositions, in otherembodiments, should provide a dosage of from about 0.0001 mg to about 70mg of compound per kilogram of body weight per day. Pharmaceuticaldosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or1 mg to about 500 mg, 1000 mg or 5000 mg, and in some embodiments fromabout 10 mg to about 500 mg of the active ingredient or a combination ofessential ingredients per dosage unit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data or subsequent clinical testing. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used such as use of liposomes,prodrugs, complexation/chelation, nanoparticles, or emulsions ortertiary templating. Such methods are known to those of skill in thisart, and include, but are not limited to, using co-solvents, such asdimethylsulfoxide (DMSO), using surfactants or surface modifiers, suchas TWEEN®, or dissolution by enhanced ionization (i.e. dissolving inaqueous sodium bicarbonate). Derivatives of the compounds, such asprodrugs of the compounds may also be used in formulating effectivepharmaceutical compositions.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedvehicle. The effective concentration is sufficient for ameliorating thesymptoms of the disease, disorder or condition treated and may beempirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as dry powder inhalers(DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets,capsules, pills, sublingual tapes/bioerodible strips, tablets orcapsules, powders, granules, lozenges, lotions, salves, suppositories,fast melts, transdermal patches or other transdermal applicationdevices/preparations, sterile parenteral solutions or suspensions, andoral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablederivatives thereof. The pharmaceutically therapeutically activecompounds and derivatives thereof are, in some embodiments, formulatedand administered in unit-dosage forms or multiple-dosage forms.Unit-dose forms as used herein refer to physically discrete unitssuitable for human and animal subjects and packaged individually as isknown in the art. Each unit-dose contains a predetermined quantity ofthe therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalvehicle. Examples of unit-dose forms include ampoules and syringes andindividually packaged tablets or capsules. Unit-dose forms may beadministered in fractions or multiples thereof. A multiple-dose form isa plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dose form. Examples ofmultiple-dose forms include vials, bottles of tablets or capsules orbottles of pints or gallons. Hence, multiple dose form is a multiple ofunit-doses which are not segregated in packaging.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in avehicle, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to thereby form a solution orsuspension, colloidal dispersion, emulsion or liposomal formulation. Ifdesired, the pharmaceutical composition to be administered may alsocontain minor amounts of nontoxic auxiliary substances such as wettingagents, emulsifying agents, solubilizing agents, pH buffering agents andthe like, for example, acetate, sodium citrate, cyclodextrinderivatives, sorbitan monolaurate, triethanolamine sodium acetate,triethanolamine oleate, and other such agents.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975 or later editions thereof.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from vehicle or carrier maybe prepared. Methods for preparation of these compositions are known tothose skilled in the art. The contemplated compositions may contain0.001%-100% active ingredient, in one embodiment 0.1-95%, in anotherembodiment 0.4-10%.

In certain embodiments, the compositions are lactose-free compositionscontaining excipients that are well known in the art and are listed, forexample, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general,lactose-free compositions contains active ingredients, a binder/filler,and a lubricant in pharmaceutically compatible and pharmaceuticallyacceptable amounts. Particular lactose-free dosage forms contain activeingredients, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

Further provided are anhydrous pharmaceutical compositions and dosageforms comprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided hereincan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are generally packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric-coated, sugar-coated or film-coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non-effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms such asfor example, capsules or tablets. The tablets, pills, capsules, trochesand the like can contain one or more of the following ingredients, orcompounds of a similar nature: a binder; a lubricant; a diluent; aglidant; a disintegrating agent; a coloring agent; a sweetening agent; aflavoring agent; a wetting agent; an enteric coating; a film coatingagent and modified release agent. Examples of binders includemicrocrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone,crospovidones, sucrose and starch and starch derivatives. Lubricantsinclude talc, starch, magnesium/calcium stearate, lycopodium and stearicacid. Diluents include, for example, lactose, sucrose, starch, kaolin,salt, mannitol and dicalcium phosphate. Glidants include, but are notlimited to, colloidal silicon dioxide. Disintegrating agents includecrosscarmellose sodium, sodium starch glycolate, alginic acid, cornstarch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose. Coloring agents include, for example, any of theapproved certified water soluble FD and C dyes, mixtures thereof; andwater insoluble FD and C dyes suspended on alumina hydrate and advancedcoloring or anti-forgery color/opalescent additives known to thoseskilled in the art. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation or mask unpleasant taste, such as, but notlimited to peppermint and methyl salicylate. Wetting agents includepropylene glycol monostearate, sorbitan monooleate, diethylene glycolmonolaurate and polyoxyethylene laural ether. Enteric-coatings includefatty acids, fats, waxes, shellac, ammoniated shellac and celluloseacetate phthalates. Film coatings include hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000 and cellulose acetatephthalate. Modified release agents include polymers such as theEudragit® series and cellulose esters.

The compound, or pharmaceutically acceptable derivative thereof, can beprovided in a composition that protects it from the acidic environmentof the stomach. For example, the composition can be formulated in anenteric coating that maintains its integrity in the stomach and releasesthe active compound in the intestine. The composition may also beformulated in combination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient may be included.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable vehicles used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicacid, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Sweetening agents include sucrose, syrups, glycerin andartificial sweetening agents such as saccharin. Wetting agents includepropylene glycol monostearate, sorbitan monooleate, diethylene glycolmonolaurate and polyoxyethylene lauryl ether. Organic acids includecitric and tartaric acid. Sources of carbon dioxide include sodiumbicarbonate and sodium carbonate. Coloring agents include any of theapproved certified water soluble FD and C dyes, and mixtures thereof.Flavoring agents include natural flavors extracted from plants suchfruits, and synthetic blends of compounds which produce a pleasant tastesensation.

For a solid dosage form, the solution or suspension, in for example,propylene carbonate, vegetable oils or triglycerides, is in someembodiments encapsulated in a gelatin capsule. Such solutions, and thepreparation and encapsulation thereof, are disclosed in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, thesolution, e.g., for example, in a polyethylene glycol, may be dilutedwith a sufficient quantity of a pharmaceutically acceptable liquidvehicle, e.g., water, to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. RE28,819 and4,358,603. Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpoly-alkylene glycol, including, but not limited to,1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer tothe approximate average molecular weight of the polyethylene glycol, andone or more antioxidants, such as butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

Parenteral administration, in some embodiments characterized byinjection, either subcutaneously, intramuscularly or intravenously isalso contemplated herein. Injectables can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution or suspension in liquid prior to injection, or asemulsions. The injectables, solutions and emulsions also contain one ormore excipients. Suitable excipients are, for example, water, saline,dextrose, glycerol or ethanol. In addition, if desired, thepharmaceutical compositions to be administered may also contain minoramounts of non-toxic auxiliary substances such as wetting or emulsifyingagents, pH buffering agents, stabilizers, solubility enhancers, andother such agents, such as for example, sodium acetate, sorbitanmonolaurate, triethanolamine oleate and cyclodextrins.

Implantation of a slow-release or sustained-release system, such that aconstant level of dosage is maintained (see, e.g., U.S. Pat. No.3,710,795) is also contemplated herein. Briefly, a compound providedherein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable vehicles used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (Tween® 80). A sequestering or chelatingagent of metal ions includes EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles; and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight, bodysurface area and condition of the patient or animal as is known in theart.

The unit-dose parenteral preparations are packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration. In oneembodiment, a therapeutically effective dosage is formulated to containa concentration of at least about 0.01% w/w up to about 90% w/w or more,in certain embodiments more than 0.1% w/w of the active compound to thetreated tissue(s).

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108;5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830;6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981;6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634.Such dosage forms can be used to provide slow or controlled-release ofone or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, liposomes, microspheres,or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled-release formulations known tothose of ordinary skill in the art, including those described herein,can be readily selected for use with the active ingredients providedherein.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the agent may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In some embodiments, a pump may beused (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwaldet al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574(1989). In other embodiments, polymeric materials can be used. In otherembodiments, a controlled release system can be placed in proximity ofthe therapeutic target, i.e., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, vol. 2, pp. 115-138 (1984). In some embodiments, a controlledrelease device is introduced into a subject in proximity of the site ofinappropriate immune activation or a tumor. Other controlled releasesystems are discussed in the review by Langer (Science 249:1527-1533(1990). The active ingredient can be dispersed in a solid inner matrix,e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The active ingredient then diffuses through the outer polymeric membranein a release rate controlling step. The percentage of active ingredientcontained in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, ina suitable solvent. The solvent may contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, an antioxidant, a buffer and abulking agent. In some embodiments, the excipient is selected fromdextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose,sucrose and other suitable agent. The solvent may contain a buffer, suchas citrate, sodium or potassium phosphate or other such buffer known tothose of skill in the art at, at about neutral pH. Subsequent sterilefiltration of the solution followed by lyophilization under standardconditions known to those of skill in the art provides the desiredformulation. In some embodiments, the resulting solution will beapportioned into vials for lyophilization. Each vial will contain asingle dosage or multiple dosages of the compound. The lyophilizedpowder can be stored under appropriate conditions, such as at about 4°C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, the lyophilized powder is added to sterile water orother suitable carrier. The precise amount depends upon the selectedcompound. Such amount can be empirically determined.

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof may beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will, in some embodiments, havemass median geometric diameters of less than 5 microns, in otherembodiments less than 10 microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

For nasal administration, the preparation may contain an esterifiedphosphonate compound dissolved or suspended in a liquid carrier, inparticular, an aqueous carrier, for aerosol application. The carrier maycontain solubilizing agents such as propylene glycol, surfactants,absorption enhancers such as lecithin or cyclodextrin, or preservatives.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7.4, withappropriate salts.

Other routes of administration, such as transdermal patches, includingiontophoretic and electrophoretic devices, and rectal administration,are also contemplated herein.

Transdermal patches, including iotophoretic and electrophoretic devices,are well known to those of skill in the art. For example, such patchesare disclosed in U.S. Pat. Nos. 6,267,983, 6,261,595, 6,256,533,6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433, and5,860,957.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono-, di- andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. The weight of a rectal suppository, inone embodiment, is about 2 to 3 gm. Tablets and capsules for rectaladministration are manufactured using the same pharmaceuticallyacceptable substance and by the same methods as for formulations fororal administration.

The compounds provided herein, or pharmaceutically acceptablederivatives thereof, may also be formulated to be targeted to aparticular tissue, receptor, or other area of the body of the subject tobe treated. Many such targeting methods are well known to those of skillin the art. All such targeting methods are contemplated herein for usein the instant compositions. For non-limiting examples of targetingmethods, see, e.g., U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359,6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082,6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252,5,840,674, 5,759,542 and 5,709,874.

In some embodiments, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art. For example, liposomeformulations may be prepared as described in U.S. Pat. No. 4,522,811.Briefly, liposomes such as multilamellar vesicles (MLV's) may be formedby drying down phosphatidyl choline and phosphatidyl serine (7:3 molarratio) on the inside of a flask. A solution of a compound providedherein in phosphate buffered saline lacking divalent cations (PBS) isadded and the flask shaken until the lipid film is dispersed. Theresulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

The compounds or pharmaceutically acceptable derivatives may be packagedas articles of manufacture containing packaging material, a compound orpharmaceutically acceptable derivative thereof provided herein, which iseffective for treatment, prevention or amelioration of one or moresymptoms of the diseases or disorders, supra, within the packagingmaterial, and a label that indicates that the compound or composition,or pharmaceutically acceptable derivative thereof, is used for thetreatment, prevention or amelioration of one or more symptoms of thediseases or disorders, supra.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disease or disorder described herein.

Dosages

In human therapeutics, the physician will determine the dosage regimenthat is most appropriate according to a preventive or curative treatmentand according to the age, weight, stage of the disease and other factorsspecific to the subject to be treated. The pharmaceutical compositions,in other embodiments, should provide a dosage of from about 0.0001 mg toabout 70 mg of compound per kilogram of body weight per day.Pharmaceutical dosage unit forms are prepared to provide from about 0.01mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 5000 mg, and in someembodiments from about 10 mg to about 500 mg of the active ingredient ora combination of essential ingredients per dosage unit form. The amountof active ingredient in the formulations provided herein, which will beeffective in the prevention or treatment of a disorder or one or moresymptoms thereof, will vary with the nature and severity of the diseaseor condition, and the route by which the active ingredient isadministered. The frequency and dosage will also vary according tofactors specific for each subject depending on the specific therapy(e.g., therapeutic or prophylactic agents) administered, the severity ofthe disorder, disease, or condition, the route of administration, aswell as age, body, weight, response, and the past medical history of thesubject.

Exemplary doses of a formulation include milligram or microgram amountsof the active compound per kilogram of subject or sample weight (e.g.,from about 1 micrograms per kilogram to about 50 milligrams perkilogram, from about 10 micrograms per kilogram to about 30 milligramsper kilogram, from about 100 micrograms per kilogram to about 10milligrams per kilogram, or from about 100 microgram per kilogram toabout 5 milligrams per kilogram).

It may be necessary to use dosages of the active ingredient outside theranges disclosed herein in some cases, as will be apparent to those ofordinary skill in the art. Furthermore, it is noted that the clinicianor treating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with subject response.

Different therapeutically effective amounts may be applicable fordifferent diseases and conditions, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such disorders, but insufficient to cause,or sufficient to reduce, adverse effects associated with the compositionprovided herein are also encompassed by the above described dosageamounts and dose frequency schedules. Further, when a subject isadministered multiple dosages of a composition provided herein, not allof the dosages need be the same. For example, the dosage administered tothe subject may be increased to improve the prophylactic or therapeuticeffect of the composition or it may be decreased to reduce one or moreside effects that a particular subject is experiencing.

In certain embodiments, administration of the same formulation providedherein may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months.

Methods of Use of the Compounds and Compositions

Methods of treating, preventing, or ameliorating one or more symptoms ofdiseases including, but not limited to, migraine, ALS, Parkinson'sdisease, extra-pyramidal disorders, depression, nausea, restless legssyndrome, insomnia, aggression, Huntington's disease, dystonia,parsomnia and hyperlactinemia using the compounds and compositions areprovided. In practicing the methods, therapeutically effective amountsof the compounds or compositions, are administered.

Also provided are methods for regulating serotonin transport using thecompounds and compositions described herein. In practicing the methods,therapeutically effective amounts of the compounds or compositions,described herein, supra, are administered.

Also provided are methods for antagonizing the 5-HT_(2B), 5-HT_(2A),5-HT₇ and 5-HT_(2C) receptors, D2 and D3 dopamine receptors and A1 andA2 adrenergic receptors using the compounds and compositions, describedherein. In practicing the methods, therapeutically effective amounts ofthe compounds or compositions, described herein, supra, areadministered.

Also provided are methods for agonizing the 5-HT_(1D), 5-HT_(1D),5-HT_(1B) and 5-HT_(1F) receptors using the compounds and compositionsdescribed herein. In practicing the methods, therapeutically effectiveamounts of the compounds or compositions, described herein, supra, areadministered.

In some embodiments, compounds of Formula (I), infra:

or salts, hydrates or solvates thereof wherein:

R₁ is (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄)perfluoroalkyl;

R₂ is alkyl, substituted alkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇;

R₃ and R₄ are independently hydrogen, deuterium, fluoro, hydroxy ormethoxy;

R₅ is hydrogen, (C₁-C₃) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₃)perfluoroalkyl;

R₆ is

R₇ is (C₁-C₄) alkyl;

R₈ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl orsubstituted benzyl;

R₉ is (C₁-C₄) alkyl or benzyl;

R₁₀ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀;

R₁₁ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃,

R₁₂ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆;

R₁₃ is hydrogen or halogen;

R₁₀₁-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;and

k is 0, 1 or 2;

n is 0, 1, 2 or 3;

provided that when R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ and R₁₃ are hydrogen and R₆is

that:

R₁ is not allyl;

provided that when R₁ and R₅ are methyl, R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ andR₁₃ are hydrogen and R₆ is

that: R₇ is not methyl, R₈ is not hydrogen and R₉ is not benzyl are usedto treat migraine. In other embodiments, compounds of Formula (I),supra, antagonize the 5-HT_(2B), 5-HT_(2A), 5-HT₇ and 5-HT_(2C)receptors, D2 and D3 dopamine receptors and A1 and A2 adrenergicreceptors. In still other embodiments, compounds of Formula (I), supra,agonize the 5-HT_(1D), 5-HT_(1D), 5-HT_(1B) and 5-HT_(1F) receptors.

In other embodiments, compounds of Formula (I), infra:

or salts, hydrates or solvates thereof wherein:

R₁ is (C₁-C₄) alkyl substituted (C₁-C₄) alkyl or (C₁-C₄) perfluoroalkyl;

R₂ is alkyl, substituted alkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇;

R₃ and R₄ are independently hydrogen, deuterium, fluoro, hydroxy ormethoxy;

R₅ is hydrogen, (C₁-C₃) alkyl or (C₁-C₃) perfluoroalkyl;

R₆ is

R₇ is (C₁-C₄) alkyl;

R₈ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl orsubstituted benzyl;

R₉ is (C₁-C₄) alkyl or benzyl;

R₁₀ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀,

R₁₁ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃,

R₁₂ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆;

R₁₃ is hydrogen or halogen;

R₁₀₁-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;and

k is 0, 1 or 2;

n is 0, 1, 2 or 3;

are used to treat or prevent ALS, Parkinson's disease, extra-pyramidaldisorders, depression, nausea, restless legs syndrome, insomnia,aggression, Huntington's disease, dystonia, parsomnia andhyperlactinemia. In other embodiments, compounds of Formula (I), supra,antagonize the 5-HT_(2B), 5-HT_(2A), 5-HT₇ and 5-HT_(2C) receptors, D2and D3 dopamine receptors and A1 and A2 adrenergic receptors. In stillother embodiments, compounds of Formula (I), supra, agonize the5-HT_(1D), 5-HT_(1D), 5-HT_(1B) and 5-HT_(1F) receptors.

In some embodiments, compounds of Formula (II), infra:

or salts, hydrates or solvates thereof wherein:

R₁ is (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄)perfluoroalkyl;

R₂ is alkyl, substituted alkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇;

R₅ is hydrogen, (C₁-C₃) alkyl, substituted (C₁-C₃) alkyl, or (C₁-C₃)perfluoroalkyl;

R₆ is

R₇ is (C₁-C₄) alkyl;

R₈ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl orsubstituted benzyl;

R₉ is (C₁-C₄) alkyl or benzyl;

R₁₀ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀;

R₁₁ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃,

R₁₂ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆;

R₁₃ is hydrogen or halogen;

R₁₀₁-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;and

k is 0, 1 or 2;

n is 0, 1, 2 or 3; are used to treat or prevent ALS, Parkinson'sdisease, extra-pyramidal disorders, depression, nausea, restless legssyndrome, insomnia, aggression, Huntington's disease, dystonia,parsomnia and hyperlactinemia. In other embodiments, compounds ofFormula (II), supra, antagonize the 5-HT_(2B), 5-HT_(2A), 5-HT₇ and5-HT_(2C) receptors, D2 and D3 dopamine receptors and A1 and A2adrenergic receptors. In still other embodiments, compounds of Formula(II), supra, agonize the 5-HT_(1D), 5-HT_(1D), 5-HT_(1B) and 5-HT_(1F)receptors.

Combination Therapy

The compounds and compositions disclosed herein may also be used incombination with one or more other active ingredients. In certainembodiments, the compounds may be administered in combination, orsequentially, with another therapeutic agent. Such other therapeuticagents include those known for treatment, prevention, or amelioration ofone or more symptoms associated with migraine, ALS, Parkinson's disease,extra-pyramidal disorders, depression, nausea, restless legs syndrome,insomnia, aggression, Huntington's disease, dystonia, parsomnia andhyperlactinemia.

It should be understood that any suitable combination of the compoundsand compositions provided herein with one or more of the abovetherapeutic agents and optionally one or more further pharmacologicallyactive substances are considered to be within the scope of the presentdisclosure. In some embodiments, the compounds and compositions providedherein are administered prior to or subsequent to the one or moreadditional active ingredients.

It should also be understood that any suitable combination of thecompounds and compositions provided herein may be used with other agentsto agonize and or antagonize the receptors mentioned above.

Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive, and theinvention is not to be limited to the details given herein, but may bemodified within the scope and equivalents of the appended claims.

All publications and patents cited herein are incorporated by referencein their entirety.

The following examples are provided for illustrative purposes only andare not intended to limit the scope of the invention.

EXAMPLES Example 1 Preparation of 1-methyl-dihydroergotamine (MAP0057)

To a solution of sodium metal (2.05 g, 89.1 mmol) in liquid ammonia (200mL) under N₂ at −78° C. was added a solution of absolute ethanol (30 mL)in anhydrous diethyl ether (40 mL) dropwise within 30 min, whereby theinitially dark blue solution is decolorized. Dihydroergotamine (5.20 g,8.90 mmol) was subsequently added to the reaction mixture. The reactionmixture was stirred at −78° C. until the material dissolved completelyand a solution of methyl iodide (2.77 mL, 44.5 mmol) in anhydrousdiethyl ether (10 mL) was added dropwise within 15 min. After stirringfor 30 min at −78° C., the clear solution was carefully heated(maintained the temperature below −30° C.) and the ammonia wasevaporated under a partial vacuum. The remaining yellow residue wasdissolved in a mixture of methylene chloride (200 mL) and saturatedaqueous NaHCO₃ (150 mL). The organic phase was washed with an aqueousNaHCO₃, brine, dried over Na₂SO₄, concentrated, and evaporated in vacuo.The residue was purified by column chromatography twice (silica gel, 40g, 95:5 methylene chloride/MeOH) to afford 1-methyl-dihydroergotamine(3.50 g, 67%) as an off-white solid: mp 216-218° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.42 (d, J=1.4 Hz, 1H), 7.39 (s, 1H), 7.28-7.12 (m, 5H), 6.92(d, J=7.0 Hz, 1H), 6.74 (d, J=0.9 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 6.43(s, 1H), 4.72 (t, J=6.1 Hz, 1H), 3.76 (s, 3H), 3.70-3.46 (m, 4H), 3.38(dd, J=14.7, 4.3 Hz, 1H), 3.23 (dd, J=14.0, 6.4 Hz, 1H), 3.13 (d,J=10.4, 2.3 Hz, 1H), 2.97 (t, J=9.2 Hz, 1H), 2.80-2.65 (m, 3H), 2.49 (s,3H), 2.43 (t, J=11.4 Hz, 1H), 2.29-2.21 (m, 1H), 2.17-1.95 (m, 3H),1.85-1.62 (m, 2H), 1.57 (s, 3H); HPLC 98.4% (AUC); ESI MS m/z 598[C₃₄H₃₉N₅O₅+H]⁺.

Example 2 Agonization of the 5-HT_(2B) Receptor with1-methyl-dihydroergotamine

A FLIPR assay was conducted to monitor agonist selectivity for1-methyl-dihydroergotamine against the 5-HT_(2B) receptor. The assay wascompleted with the 1-methyl-dihydroergotamine at final concentrations of1.0 μM, 10.0 nM, and 2.0 nM. Percentage activation values weredetermined for 1-methyl-dihydroergotamine on the 5-HT_(2B) receptor.Agonist selectivity was determined upon initial addition of for1-methyl-dihydroergotamine followed by a 5 minute incubation at 25° C.Following compound incubation, reference agonists were added at EC₈₀.Agonist percentage activation determinations were obtained by assaying1-methyl-dihydroergotamine and referencing the E_(max) control for the5-HT_(2B) receptor. The assay was performed by GPCR Profiler™ ServiceLaboratory, St. Charles, Mo., Millipore, Inc.

The data is summarized in FIG. 1 which illustrates potent agonism of the5-HT_(2B) receptor for the alpha-Me-5HT experimental control (knownpotent agonist of EC₅₀ of 0.20 nM) and pergolide (EC₅₀ of 10 nM) acompound withdrawn from the market due to cardiovascular safetyconcerns. Ergotamine (EC₅₀ of 160 nM) and dihydroergotamine ((EC₅₀ of260 nM) are several orders of potency less potent that the control andpergolide, but are still agonists. Importantly, MAP0057(1-methyl-dihydroergotamine) shows no agonist activity.

Example 3 Competitive Antagonization of the 5-HT_(2B) Receptor with1-methyl-dihydroergotamine

A FLIPR assay was conducted to monitor antagonist selectivity for1-methyl-dihydroergotamine against the 5-HT_(2B) receptor. The assay wascompleted with the 1-methyl-dihydroergotamine at final concentrations of1.0 M, 10.0 nM, and 2.0 nM. Percentage inhibition values were determinedfor 1-methyl-dihydroergotamine on the 5-HT_(2B) receptor. Antagonistpercentage inhibition determinations were obtained by assaying1-methyl-dihydroergotamine and referencing the E_(max) control for the5-HT_(2B) receptor. The assay above was performed by GPCR Profiler™Service Laboratory, St. Charles, Mo., Millipore, Inc.

The data is summarized in FIG. 2 which illustrates a reduction inactivity with increasing concentrations of 1-methyl-dihydroergotamineshowing that MAP0057 (1-methyl-dihydroergotamine) is a potent (IC₅₀ of16 nM) antagonist at the 5-HT_(2B) receptor.

Example 4 Agonization of the 5-HT₂, Receptor with1-methyl-dihydroergotamine

The assay was performed analogously to the assay described in Example 2.Pergolide, dihydroergotamine, sumatriptan and MAP0057(1-methyl-dihydroergotamine) have no agonist activity at the 5-HT_(2c)receptor while alpha-Me-5-HT (EC₅₀ of 45 nM) and ergotamine (EC₅₀ of 5μM) have significant agonist activity at the 5-HT_(2c) receptor.

Example 5 Competitive Antagonization of the 5-HT₂, Receptor with1-methyl-dihydroergotamine

The assay was performed analogously to the assay described in Example 3.Pergolide (IC₅₀ of 5 μM), dihydroergotamine (IC₅₀ of 280 nM) and MAP0057(1-methyl-dihydroergotamine, IC₅₀ of 460 nM) are significant antagonistsof the 5-HT_(2c) receptor while sumatriptan has no antagonist activityat the 5-HT_(2c) receptor.

Example 6 Agonization of the D2 Receptor with 1-methyl-dihydroergotamine

The assay was performed analogously to the assay described in Example 2.Dihydroergotamine, sumatriptan, ergotamine and MAP0057(1-methyl-dihydroergotamine) have no agonist activity at the D2 receptorwhile pergolide (EC₅₀ of 8.5 nM) and dopamine (EC₅₀ of 62 nM) havesignificant agonist activity at the D2 receptor.

Example 7 Competitive Antagonization of the D2 Receptor with1-methyl-dihydroergotamine

The assay was performed analogously to the assay described in Example 3.Sumatriptan (IC₅₀ of >than 10 μM), dihydroergotamine (IC₅₀ of 0.7 nM),ergotamine (IC₅₀ of 0.6 nM) and MAP0057 (1-methyl-dihydroergotamine,IC₅₀ of 1.2 nM) are significant antagonists of the D2 receptor.

Example 8 Agonization of the 5-HT_(1A) Receptor with1-methyl-dihydroergotamine

A cell based assay (cAMP modulation with HTRF detection) was conductedto monitor agonist activity of test compounds at the 5-HT_(1A) receptor,summarized in FIG. 3. Test compounds were serially diluted to provide awide concentration range sufficient to calculate EC₅₀. The cAMPconcentration was determined and results are expressed as a percent ofthe control response to 100 nM 8-OH-DPAT (control agonist).1-methyl-dihydroergotamine displayed a strong agonist activity with EC₅₀of 16 nM.

Example 9 Antagonization of the 5-HT₇ Receptor with1-methyl-dihydroergotamine

The assay was performed analogously to the assay described in Example 8.Antagonist activity of test compounds at the 5-HT₇ receptor, usingserotonin as a control reference agonist, was measured. The results aresummarized in FIG. 4. Test compounds were serially diluted to provide awide concentration range sufficient to calculate IC₅₀. The results areexpressed as a percent of the control response to 300 nM serotonin.1-methyl-dihydroergotamine displayed a strong antagonist activity withIC₅₀ of 69 nM.

Example 10 Agonization of the 5-HT_(1B) Receptor with1-methyl-dihydroergotamine

A membrane based GTPγS assay was conducted to monitor agonist activityof test compounds at the 5-HT_(1B) receptor, summarized in FIG. 5. Testcompounds were serially diluted to provide a wide concentration rangesufficient to calculate EC₅₀. The results are expressed as a percent ofactivation. 5-CT was used as a reference agonist.1-methyl-dihydroergotamine displayed a strong agonist activity with EC₅₀of 1.02 nM.

Example 11 Agonization of the 5-HT_(1D) Receptor with1-methyl-dihydroergotamine

The assay was performed analogously to the assay described in Example10, at the 5-HT_(1B) receptor. The results are summarized in FIG. 6.5-CT was used as a reference agonist. 1-methyl-dihydroergotaminedisplayed a strong agonist activity with EC₅₀ of 0.45 nM.

What is claimed is:
 1. A compound of Formula (I):

or pharmaceutically acceptable salts, hydrates or solvates thereofwherein: R₁ is (C₁-C₄) alkyl or (C₁-C₄) perfluoroalkyl; R₂ is alkyl,substituted alkyl, acyl, substituted acyl, halo, heteroalkyl,substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁,—NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —OC(O)R₁₀₇; R₃ and R₄ areindependently hydrogen, deuterium, fluoro, hydroxy or methoxy; R₅ ishydrogen, (C₁-C₃) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₃)perfluoroalkyl; R₆ is

R₇ is isopropyl, sec-butyl, isobutyl, or t-butyl; R₈ is hydrogen,(C₁-C₄) alkyl substituted (C₁-C₄) alkyl, benzyl or substituted benzyl;R₉ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl,(C₂-C₄) alkenyl or (C₂-C₄) alkynyl; R₁₀ is hydrogen, OH, ═O, (C₁-C₄)alkyl, (C₁-C₄) substituted alkyl, —CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀, R₁₁ ishydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl, —CO₂R₁₁₁ or—CONR₁₁₂R₁₁₃, R₁₂ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄)substituted alkyl, —CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆; R₁₃ is hydrogen or halogen;R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈, R₁₀₉, R₁₁₀, R₁₁₁, R₁₁₂,R₁₁₃, R₁₁₄, R₁₁₅ and R₁₁₆ are independently hydrogen, alkyl, substitutedalkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;and k is 0, 1 or 2; n is 0, 1, 2 or 3; wherein substituted withreference to a saturated carbon atom is limited to —R^(a), halo, —O⁻,═O, —OR^(b), —SR^(b), —S⁻, ═S, —NR^(c)R^(c), ═NR^(b), ═N—OR^(b),trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b),—S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻,—OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)),—C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻, —C(O)OR^(b),—C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b),—OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b),—NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)s are taken together with the nitrogen atomto which they are bonded form a 4-, 5-, 6- or 7-memberedcycloheteroalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S; and substituted with reference to an unsaturated carbon atomor an nitrogen atom in a heteroalkyl group is limited to —R^(a), halo,—O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl, —CF₃, —CN,—OCN, —SCN, —NO, —NO₂, —N₃, —S(O)₂R^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c) where R^(a), R^(b) and R^(c) are as definedabove; provided that when R₁ and R₅ are methyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

 that: R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not n-propyl;R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl; R₇ isnot isopropyl, R₈ is not hydrogen and R₉ is not isopropyl; provided thatwhen R₁ and R₅ are methyl, R₃ is —OCH₃, R₂, R₄, R₁₀, R₁₁, R₁₂ and R₁₃are hydrogen and R₆ is

 that: R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;provided that when R₁ and R₅ are methyl, R₂, R₃, R₄, R₁₀, R₁₁ and R₁₂are hydrogen, R₁₃ is bromine and R₆ is

 that: R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl; providedthat when R₁ is n-propyl, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁ and R₁₂ arehydrogen, R₁₃ is bromine and R₆ is

 that: R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;provided that when R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ and R₁₃ are hydrogen and R₆is

 that: R₁ is not allyl; provided that when R₁ is ethyl, R₅ is methyl,R₂, R₃, R₄, R₁₀, R₁₁, R₁₂ and R₁₃ are hydrogen and R₆ is

 that: R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;provided that when R₁ is n-propyl, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ is hydrogen and R₆ is

 that: R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;provided that when R₁ is CH₂OCOCH₃, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁,R₁₂ and R₁₃ are hydrogen and R₆ is

 that: R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;provided that when R₁ is CH₂OH, R₅ is methyl, R₂, R₃, R₄, R₁₀, R₁₁, R₁₂and R₁₃ are hydrogen and R₆ is

 that: R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isobutyl;R₇ is not isopropyl, R₈ is not hydrogen and R₉ is not isopropyl;provided that when R₁ and R₅ are methyl and R₂, R₃ and R₄ are hydrogenthat: R₆ is not

provided that when R₁ and R₅ are methyl and R₂, R₃ and R₄ are hydrogenthat: R₆ is not

 provided that when R₁ and R₅ are methyl and R₂, R₃ and R₄ are hydrogenthat: R₆ is not


2. The compound of claim 1, wherein R₆ is

R₇ is isopropyl, R₈ is hydrogen or methyl, R₉ is n-propyl, isopropyl orisobutyl and R₁₀, R₁₁ and R₁₂ are hydrogen.
 3. The compound of claim 1,wherein R₁ is (C₁-C₄) alkyl or (C₁-C₄) perfluoroalkyl and R₆ is


4. The compound of claim 1, wherein R₁ is —CH₃, —C₂H₅, —C₃H₇, i-C₃H₇,—CF₃, —C₂F₅, —C₃F₇ or i-C₃F₇ and R₆ is


5. The compound of claim 1, wherein R₁ is —CH₃, —C₂H₅, —C₃H₇, i-C₃H₇,—CF₃, —C₂F₅, —C₃F₇ or i-C₃F₇, R₂ is (C₁-C₄) alkyl, (C₁-C₄) substitutedalkyl, (C₁-C₄) acyl, (C₁-C₄) substituted acyl, halo, —NO₂, —OR₁₀₁,—NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —OC(O)R₁₀₇, n is 0 or 1, R₃ and R₄are independently hydrogen or deuterium, R₅ is —CH₃, —C₂H₅, —C₃H₇, —CF₃,C₂F₅ or —C₃F₇, R₆ is

R₁₀, R₁₁ and R₁₂ are independently hydrogen, OH or (C₁-C₄) alkyl; andR₁₃ is hydrogen or bromine.
 6. The compound of claim 1, wherein R₁ is—CH₃, —C₂H₅, -nC₃H₇, —CF₃, C₂F₅ or -nC₃F₇, R₂ is (C₁-C₂) alkyl, (C₁-C₂)substituted alkyl, halo, —NO₂, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅,—CO₂R₁₀₆ or —OC(O)R₁₀₇, n is 0, R₃ and R₄ are independently hydrogen ordeuterium, R₅ is —CH₃ or —CF₃, R₆ is

R₇ is isopropyl, R₈ is hydrogen or methyl, R₉ is n-propyl, isopropyl orisobutyl, R₁₀, R₁₁ and R₁₂ are hydrogen; and R₁₃ is hydrogen.
 7. Apharmaceutical composition comprising the compound of claim 1 and apharmaceutically acceptable vehicle.